Broadening the chemical diversity of oxidovanadium(V) complexes for targeting neglected tropical diseases

Chagas disease and Leishmaniasis, caused by Trypanosoma cruzi and Leishmania spp., respectively, are highly prevalent neglected tropical diseases (NTDs) that pose significant global health challenges. In our pursuit of effective vanadium-based therapeutics against these diseases, we previously developed several series of oxidovanadium(V) complexes featuring bidentate bioactive ligands and Schiff base tridentate ligands. The current study extends our previous research by incorporating in the same molecule, a tridentate bromo-substituted isonicotinyl hydrazone Schiff base ligand, BrIS, and a 8-hydroxyquinoline derivative (L), leading to the synthesis and comprehensive characterization of five new complexes, [V^VO(BrIS-2H)(L-H)]. Most of new complexes exhibited activity in the micromolar range against the infective trypomastigote form of T. cruzi (EC_{50, 24h}: 0.73-7.95 μM) and against L. infantum promastigotes (IC_{50, 5 days}: 1.14-1.16 μM) and some of them showed good selectivity indexes towards the parasites (SI up to 52). Notably, the vanadium uptake by the parasites was higher for the new [V^VO(BrIS-2H)(L-H)] compounds compared to [V^VO(IN-2H)(L-H)] analogues previously developed, where IN is the structurally related 2-hydroxy-1-naphtaldehyde isonicotinoylhydrazone ligand, with accumulation in the soluble cell fraction. High-dose incubations resulted in trypanocidal effects and suggested the generation of reactive oxygen species (ROS). Further analysis revealed that [V^VO(BrIS-2H)(L-H)] complexes induced a higher percentage of apoptosis, whereas the [V^VO(IN-2H)(L-H)] series was associated with autophagic cell death. These findings highlight the potential of the [V^VO(BrIS-2H)(L-H)] series as promising anti-T. cruzi agents and underscore the need for further research to optimize their therapeutic efficacy and explore their mechanisms of action.